Growing blood vessels in a dish
A new technique that enables doctors to recreate a patient's disease in a dish and it has been pioneered at Cambridge University where cardiologist Sanjay Sinha is working on disorders of blood vessels and he told Chris Smith about his work...
Sanjay - We take advantage of making stem cells from patients who have diseases. We can actually take a skin biopsy from these patients and using those skin cells turn them into stem cells, and then we can use these stem cells to generate blood vessel tissues. Basically smooth muscles cells are the ones we primarily study and these are the cells that form the walls of most blood vessels.
We started off looking at aortic aneurysms and we focused on a condition called Marfan syndrome. This is a genetic disorder, so it runs in families. People who have Marfan's have overgrowth of their long bones, hyperextensible joints and, in fact, it's speculated that Abraham Lincoln might actually have had Marfan syndrome. That's the sort of typical appearance of somebody.
But the biggest problem that these people face is the development of aortic aneurysms. The aorta is the biggest blood vessel in the body. It's like a large hosepipe coming out of your heart and if that ruptures or tears, it's absolutely catastrophic for the patient.
Chris - What fraction of people who are affected by Marfan's actually get that problem?
Sanjay - Well a large percentage of them actually. But the majority of them will have increasing aortic size. And, at the moment, the only treatment that's effective for preventing rupture or tearing of these vessels is surgery. There's no effective medical treatment at the moment and that's what we'd like to do is to come up with a new treatment that can actually prevent aneurysms and prevent such drastic surgery from being needed.
Chris - And so using your technique, does that mean we'll gain potentially more insight into why the disease does what it does?
Sanjay - That's exactly what we want to do. The smooth muscles cells that we make from the stem cells of patients, we can see the same abnormalities in the culture dish that we see in a patient's aorta. So the abnormalities were to do with the breakdown of extracellular matrix connective tissues, increased stiffness of the smooth muscle cells, the increasing smooth muscle cell death, we see all that in our culture dish as well.
So we can use this system now to study the molecular mechanisms - what might be causing those abnormalities? We can also use it as a screen to say what new medicines or drugs can we use to try and prevent those abnormalities.
Chris - Can we take a look at the laboratory where you're making these diseased blood vessels in dishes?
Sanjay - Off course - let's go... We keep the cells in this incubator at 37 degrees. So if you have a look down here, you'll see round patches of cells. Now these are stem cells that we have generated from patients with Marfan syndrome.
Chris - I'm looking down the microscope and I'm seeing blobs. They look like little islands if I was to look at an archipelago of islands in the ocean. What am I seeing?
Sanjay - You're seeing stem cell colonies - these are collections of cells. As they grow bigger we can then treat them with cocktails of growth factors and then these will eventually make smooth muscle cells.
Chris - How do you know when they've turned into a muscle cell?
Sanjay - They change their appearance. They'll start to look like long spindles, so very different in appearance to what we see here, in fact, much bigger. And, in fact, if you then stimulate them you can actually see the muscles contract.
Chris - Goodness! And once you've got them into muscle, how do you then sort of start asking questions of them about the disease they would be harbouring were they in a patient?
Sanjay - We can do studies looking at the different proteins that are expressed. We can look at changes in the DNA, whether the cells are alive or whether they're dying. And using all of these approaches we can see whether the cells are healthy as you might expect in a healthy vessel, or whether they're reproducing the abnormalities that we see in patients who have Marfan syndrome.
Chris - Sanjay Sinha. But what does a discovery like this mean for a person who actually has the condition?
Shona - My name is Shona Cobb and I have Marfan syndrome, and I write a blog called Shona Louise. When I was growing up I went to Great Ormond Street a lot and to me that was just sort of a fun day out. That's how I associated it.
Chris - This is the hospital for kids in London?
Shona - Yeah. And then as I grew older I leant more about it. I learnt about our family history and what happened with my uncle and my grandad who both suffered aortic dissections when they were in their thirties, so I learnt how important it was. And then this year it became more central in my life as we discovered that my measurements were progressing towards the point where they would operate.
Chris - So this is the main blood vessel coming out of the heart in you is stretching now?
Shona - Yeah. My aortic root is getting quite close to the point where they usually say it's time to step in.
Chris - And what will that mean?
Shona - It will mean major open heart surgery. Having a whole part of my aorta replaced to remove the part that has widened to stop it from bursting. So it will be quite extensive surgery, especially for someone of a young age.
Chris - How old are you?
Shona - I'm nineteen.
Chris - Now when you hear about a piece of research like Sanjay has done here being reported about the condition that is very close to your heart - no pun intended - what goes through your mind?
Shona - It's amazing. For someone like me it's going to be up there as a day I will remember for the rest of my life. And I'm really not exaggerating because this is big news for me and many others. We have a rare condition that we often go to the doctors and they don't know what it is or they don't know enough about it and they sit there and google it in front of us. So to have someone say that they've spend time and energy looking into our condition and they've actually found something which is a big step forward, you know, it's amazing.
Chris - What about the point though, that for many people with these sorts of conditions, it will be too late to stop them from getting the kinds of complications like you have got?
Shona - Yeah, I've been thinking about that a lot because, obviously, it is too late for me and it's too late for some of my family as well, but I think it brings hope for the next generations to come. And there's a lot of people who have children who have only just been diagnosed with it or having babies and wondering if they have it. To be able to have someone say, you know things might be different for them is what we want.
Chris - Shona Cobb. So what new avenues has this ability to reproduce a patient's disease in a dish delivered to us. Sanjay Sinha again...
Sanjay - In the majority of people with Marfan's, the gene is fibrillin-1, and mutations in of fibrillin-1. What happens is there's a lot less fibrillin-1 in the aorta and there's also degradation and breakdown of other connective tissues that leads to weakening of the vessel wall and there's also loss of smooth muscle cells. And what our work has shown is that there's another pathway that we've identified mediated through a protein called P38 that's important for smooth muscle cell death. And P38 is overactive in Marfan sydrome, and if we actually block it we can rescue this smooth muscle cell death.
Chris - And that's what this new approach is showing you?
Sanjay - That's what the new approach has shown us. And I think it's really important and actually really exciting because there are medicines available that drug companies are developing to block P38. These have been used in clinical trials in other patients with other conditions so we know these drugs are safe. They've never been tried in patients with Marfan syndrome, and I think this is really exciting because our study suggests that we could use these drugs that we know are relatively safe. So very close, I think, to clinical trials using this approach.